Zoonofic infecfions rennain an important threat to human health. In this merit extension, we will confinue to identify primate reservoirs of human disease, elucidate mechanisms of pathogen cross-species transmission and examine why zoonofic infecfions are frequently associated with severe illness. Specifically, we propose: 1. To identify the ape reservoirs of HIV-1 groups O and P. While the origins of H|V-1 groups M and N have been traced to distinct chimpanzee communities in southern Cameroon, the precursors of HIV-1 groups O and P are still uncertain. This is because SIVcpz/SIVgor strains closely related to these lineages have not yet been identified. Large numbers of chimpanzees and gorillas in west central Africa have not yet been screened for SIV. We will thus conduct molecular epidemiological studies in these areas, determining the prevalence, distribution and genetic diversity of SIVcpz/SIVgor infections. We expect these studies to identify the geographic and species origins of HIV-1 groups O and P. 2. To determine the natural history of SIVgor infection. We recently identified one area in southwestern Cameroon that represents a hotspot of SIVgor infection (25% prevalence). Prospective studies of three gorilla groups at this site identified 29 SIVgor positive individuals, including two who only recently became infected. We will continue to follow these groups prospectively, tracking both infected and uninfected individuals, characterizing their viruses, and determining the impact of SIVgor infection on their population size. This will allow us to determine whether SIVgor, like HIV-1 and SIVcpz, is pathogenic in its natural host. 3. To determine whether wild apes serve as a recurrent source for human infection. The recent discovery of HIV-1 group P strongly suggests that cross-species transmissions of ape SIVs are still ongoing. Using newly developed diagnostic assays, we will test humans who live in close proximity to wild apes for SIV zoonoses, focusing on populations with known exposure to primates. We will also screen humans for ape Plasmodium parasites, having recently discovered the origin of human P. falciparum in gorillas. The goal is to determine whether and to what extent wild apes represent a recurrent source of human pathogens. 4. To identify viral determinants of cross-species transmission and human adaptation. Host specific restriction factors, in particular tetherin, pose major hurdles to SIV cross-species transmission. However, 12 independent HIV-1 and HIV-2 introductions indicate that these hurdles are not insurmountable. We will continue to evaluate tetherin and other restriction factors as barriers to cross-species transmission and secondary spread. In particular, we will examine whether the lack of an effective tetherin antagonism contributed to the inability of the rare groups of HIV-1 and HIV-2 to spread epidemically, and whether the apparent absence of SIVcpzPfe infections in humans can be explained by a similar mechanism.